Transmembrane electrical potential difference regulates Na+/HCO3- cotransport and intracellular pH in hepatocytes.

Fitz, John; Lidofsky, Steven D.; Xie, Ming; Scharschmidt, Bruce F.

doi:10.1073/pnas.89.9.4197

Cited by 16 publications

(20 citation statements)

References 25 publications

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“…NBCe2 is strongly expressed in the liver, where it is localized to hepatocytes and intrahepatic cholangiocytes in bile ducts (6). The hepatic expression of NBCe2 is consistent with the electrophysiological observation (99, 100) that HCO 3 − -dependent acid extrusion in hepatocytes is governed by electrogenic Na,HCO 3 -cotransport. Other cells that express NBCe2 include uroepithelial cells and renal collecting duct intercalated cells (6, 81), choroid plexus epithelial cells (46, 81).…”

Section: The Cloning Erasupporting

confidence: 88%

Cation‐Coupled Bicarbonate Transporters

Aalkjær

Boedtkjer

Choi

et al. 2014

Comprehensive Physiology

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Cation-coupled HCO3− transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3− and associated with Na+ and Cl− movement. The first Na+-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na+-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na+-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3− transporters of the SLC4-family.

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Section: The Cloning Erasupporting

confidence: 88%

Cation‐Coupled Bicarbonate Transporters

Aalkjær

Boedtkjer

Choi

et al. 2014

Comprehensive Physiology

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“…An immediate effect would be to decrease the driving force for proton entry into cells. However, depolanization has also been shown to cause an alkaline shift by modulating Na+-lactate/H+-lactate exchange (119,120) and Na+/HCO3 cotransport (121). Consistent with this hypothesis, experimental results using voltagesensitive dyes suggest that the membrane potentials in drug-resistant cells are different from those in drug-sensitive cells (122,123).…”

supporting

confidence: 69%

Cell biological mechanisms of multidrug resistance in tumors.

Simon

Schindler

1994

Proc. Natl. Acad. Sci. U.S.A.

349

214

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“…Under physiologic conditions, opening of K ϩ channels by glucagon and closure by insulin modulates many liver cell functions including solute uptake, gluconeogenesis, and intracellular pH regulation through effects on membrane potential difference (1,2). However, these regulatory pathways are disrupted by metabolic stress associated with exposure to toxins including ethanol (3) or by ischemia related to hypoperfusion or organ preservation which can result in liver cell injury and necrosis (4).…”

mentioning

confidence: 99%

Metabolic Stress Opens K+ Channels in Hepatoma Cells through a Ca2+- and Protein Kinase Cα-dependent Mechanism

Wang

Sostman

Roman

et al. 1996

Journal of Biological Chemistry

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K ϩ efflux through ion channels represents a key point for regulation of liver cell transport and metabolism. Under physiologic conditions, opening of K ϩ channels by glucagon and closure by insulin modulates many liver cell functions including solute uptake, gluconeogenesis, and intracellular pH regulation through effects on membrane potential difference (1, 2). However, these regulatory pathways are disrupted by metabolic stress associated with exposure to toxins including ethanol (3) or by ischemia related to hypoperfusion or organ preservation which can result in liver cell injury and necrosis (4). Many of the effects of ischemia result from hypoxia which inhibits oxidative phosphorylation and depletes cellular ATP stores. Pharmacologic agents including 2,4-dinitrophenol (DNP) 1 which uncouples oxidative metabolism and 2-deoxy-Dglucose (2-DG) which impairs glycolysis have been useful models of ATP depletion because in liver cells they produce biochemical changes similar to those caused by hypoxia (5).At the cellular level, one of the earliest effects of oxidative stress is dissipation of transmembrane cation gradients (6) and sustained release of K ϩ ions (7). In isolated livers, oxidative stress stimulates K ϩ efflux, increasing the concentration of K ϩ in perfusate from 5.6 to 13.1 mM (8). Efflux of K ϩ appears early, preceding release of aminotransferases, and correlates closely with the fall in ATP levels (8). Net loss of K ϩ ions is related in part to inhibition of Na ϩ /K ϩ pump activity (4, 6). However, studies of other cell types have identified an additional and quantitatively important pathway for hypoxia-induced K ϩ efflux mediated by opening of K ϩ channels. In cardiovascular tissues, K ϩ channel opening represents an important adaptive response to stress since membrane hyperpolarization results in vasodilation and restoration of blood flow (9). Two modes of regulation have been identified, including opening of glibenclamide-sensitive K ATP channels where ATP itself is responsible for channel gating (9 -11) and opening of Ca 2ϩ -sensitive K ϩ channels in tissues where metabolic inhibition increases intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (12, 13). It is notable that metabolic inhibition releases Ca 2ϩ from intracellular stores of liver cells (6,14,15), and the resulting increase in [Ca 2ϩ ] i is characteristic of many forms of liver cell injury (4).The purpose of the current studies was to evaluate the relationship between cellular metabolism and membrane K ϩ permeability in HTC cells, a model liver cell line. Different models of metabolic inhibition increased K ϩ conductance 30-fold or more through activation of apamin-sensitive SK Ca channels. Channel opening appears to occur through a mechanism distinct from cardiovascular tissues and involves translocation of protein kinase C␣ (PKC␣) from cytosol to membrane. Moreover, intracellular perfusion with purified PKC␣ activates currents in the absence of metabolic inhibition, suggesting that the ␣ isoform of PKC may be selectively ...

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Transmembrane electrical potential difference regulates Na+/HCO3- cotransport and intracellular pH in hepatocytes.

Cited by 16 publications

References 25 publications

Cation‐Coupled Bicarbonate Transporters

Cation‐Coupled Bicarbonate Transporters

Cell biological mechanisms of multidrug resistance in tumors.

Metabolic Stress Opens K+ Channels in Hepatoma Cells through a Ca2+- and Protein Kinase Cα-dependent Mechanism

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